Rituximab therapy for juvenile-onset systemic lupus erythematosus

Rituximab (RTX), an anti-CD20 monoclonal antibody, has been proposed for use in the therapy of systemic lupus erythematosus (SLE). We present the initial long-term experience of the safety and efficacy of rituximab for treatment of SLE in children. Eighteen patients (mean age 14 ± 3 years) with severe SLE were treated with rituximab after demonstrating resistance or toxicity to conventional regimens. There was a predominance of female (16/18) and ethnic African (13/18) patients. All had lupus nephritis [World Health Organization (WHO) classes 3–5] and systemic manifestations of vasculitis. Clinical disease activity of the SLE was scored with the SLE-disease activity index 2K (SLEDAI-2K). Patients were followed-up for an average of 3.0 ± 1.3 years (range 0.5 to 4.8 years). B-cell depletion occurred within 2 weeks in all patients and persisted for up to 1 year in some. Clinical activity scores, double-stranded DNA (dsDNA) antibodies, renal function and proteinuria [urine protein to creatinine ratio (Upr/cr)] improved in 93% of the patients. Five patients required multiple courses of RTX for relapse, with B-cell repopulation. One died of infectious endocarditis related to severe immunosuppression. In conclusion, our data support the efficacy of rituximab as adjunctive treatment for SLE in children. Although rituximab was well tolerated by the majority of patients, randomized controlled trials are required to establish its long-term safety and efficacy

Ouabain protects against adverse developmental programming of the kidney

The kidney is extraordinarily sensitive to adverse fetal programming. Malnutrition, the most common form of developmental challenge, retards the formation of functional units, the nephrons. The resulting low nephron endowment increases susceptibility to renal injury and disease. Using explanted rat embryonic kidneys, we found that ouabain, the Na,K-ATPase ligand, triggers a calcium–nuclear factor-κB signal, which protects kidney development from adverse effects of malnutrition. To mimic malnutrition, kidneys were serum deprived for 24 h. This resulted in severe retardation of nephron formation and a robust increase in apoptosis. In ouabain-exposed kidneys, no adverse effects of serum deprivation were observed. Proof of principle that ouabain rescues development of embryonic kidneys exposed to malnutrition was obtained from studies on pregnant rats given a low-protein diet and treated with ouabain or vehicle throughout pregnancy. Thus, we have identified a survival signal and a feasible therapeutic tool to prevent adverse programming of kidney development

Nutrition in children with CRF and on dialysis

The objectives of this study are: (1) to understand the importance of nutrition in normal growth; (2) to review the methods of assessing nutritional status; (3) to review the dietary requirements of normal children throughout childhood, including protein, energy, vitamins and minerals; (4) to review recommendations for the nutritional requirements of children with chronic renal failure (CRF) and on dialysis; (5) to review reports of spontaneous nutritional intake in children with CRF and on dialysis; (6) to review the epidemiology of nutritional disturbances in renal disease, including height, weight and body composition; (7) to review the pathological mechanisms underlying poor appetite, abnormal metabolic rate and endocrine disturbances in renal disease; (8) to review the evidence for the benefit of dietetic input, dietary supplementation, nasogastric and gastrostomy feeds and intradialytic nutrition; (9) to review the effect of dialysis adequacy on nutrition; (10) to review the effect of nutrition on outcome

Decreased renal function in overweight and obese prepubertal children

BACKGROUND: Obesity is a potentially modifiable risk factor for the development and progression of kidney disease, both in adults and children. We aim to study the association of obesity and renal function in children, by comparing estimated glomerular filtration rate (eGFR) in nonoverweight and overweight/obese children. Secondarily, we aim to evaluate the accuracy of equations on eGFR estimation when compared to 24-h urinary creatinine clearance (CrCl). METHODS: Cross-sectional study of 313 children aged 8-9 y, followed in the birth cohort Generation XXI (Portugal). Creatinine and cystatin C, GFR estimated by several formulas and CrCl were compared in 163 nonoverweight and 150 overweight/obese, according to World Health Organization growth reference. RESULTS: Overweight/obese children had significantly lower eGFR, estimated by all methods, except for CrCl and revised Schwartz formula. Despite all children having renal function in the normal range, eGFR decreased significantly with BMI z-score (differences ranging from -4.3 to -1.1 ml/min/1.73 m(2) per standard deviation of BMI). The Zappitelli combined formula presented the closest performance to CrCl, with higher correlation coefficients and higher accuracy values. CONCLUSION: Young prepubertal children with overweight/obesity already present significantly lower GFR estimations that likely represent some degree of renal impairment associated with the complex deleterious effects of adiposity

Acute kidney injury in children

Acute kidney injury (AKI) (previously called acute renal failure) is characterized by a reversible increase in the blood concentration of creatinine and nitrogenous waste products and by the inability of the kidney to regulate fluid and electrolyte homeostasis appropriately. The incidence of AKI in children appears to be increasing, and the etiology of AKI over the past decades has shifted from primary renal disease to multifactorial causes, particularly in hospitalized children. Genetic factors may predispose some children to AKI. Renal injury can be divided into pre-renal failure, intrinsic renal disease including vascular insults, and obstructive uropathies. The pathophysiology of hypoxia/ischemia-induced AKI is not well understood, but significant progress in elucidating the cellular, biochemical and molecular events has been made over the past several years. The history, physical examination, and laboratory studies, including urinalysis and radiographic studies, can establish the likely cause(s) of AKI. Many interventions such as ‘renal-dose dopamine’ and diuretic therapy have been shown not to alter the course of AKI. The prognosis of AKI is highly dependent on the underlying etiology of the AKI. Children who have suffered AKI from any cause are at risk for late development of kidney disease several years after the initial insult. Therapeutic interventions in AKI have been largely disappointing, likely due to the complex nature of the pathophysiology of AKI, the fact that the serum creatinine concentration is an insensitive measure of kidney function, and because of co-morbid factors in treated patients. Improved understanding of the pathophysiology of AKI, early biomarkers of AKI, and better classification of AKI are needed for the development of successful therapeutic strategies for the treatment of AKI

Epidemiology of chronic kidney disease in children

In the past 30 years there have been major improvements in the care of children with chronic kidney disease (CKD). However, most of the available epidemiological data stem from end-stage renal disease (ESRD) registries and information on the earlier stages of pediatric CKD is still limited. The median reported incidence of renal replacement therapy (RRT) in children aged 0–19 years across the world in 2008 was 9 per million of the age-related population (4–18 years). The prevalence of RRT in 2008 ranged from 18 to 100 per million of the age-related population. Congenital disorders, including congenital anomalies of the kidney and urinary tract (CAKUT) and hereditary nephropathies, are responsible for about two thirds of all cases of CKD in developed countries, while acquired causes predominate in developing countries. Children with congenital disorders experience a slower progression of CKD than those with glomerulonephritis, resulting in a lower proportion of CAKUT in the ESRD population compared with less advanced stages of CKD. Most children with ESRD start on dialysis and then receive a transplant. While the survival rate of children with ERSD has improved, it remains about 30 times lower than that of healthy peers. Children now mainly die of cardiovascular causes and infection rather than from renal failure

Pathogenesis of adolescent idiopathic scoliosis in girls - a double neuro-osseous theory involving disharmony between two nervous systems, somatic and autonomic expressed in the spine and trunk: possible dependency on sympathetic nervous system and hormones with implications for medical therapy

Anthropometric data from three groups of adolescent girls - preoperative adolescent idiopathic scoliosis (AIS), screened for scoliosis and normals were analysed by comparing skeletal data between higher and lower body mass index subsets. Unexpected findings for each of skeletal maturation, asymmetries and overgrowth are not explained by prevailing theories of AIS pathogenesis. A speculative pathogenetic theory for girls is formulated after surveying evidence including: (1) the thoracospinal concept for right thoracic AIS in girls; (2) the new neuroskeletal biology relating the sympathetic nervous system to bone formation/resorption and bone growth; (3) white adipose tissue storing triglycerides and the adiposity hormone leptin which functions as satiety hormone and sentinel of energy balance to the hypothalamus for long-term adiposity; and (4) central leptin resistance in obesity and possibly in healthy females. The new theory states that AIS in girls results from developmental disharmony expressed in spine and trunk between autonomic and somatic nervous systems. The autonomic component of this double neuro-osseous theory for AIS pathogenesis in girls involves selectively increased sensitivity of the hypothalamus to circulating leptin (genetically-determined up-regulation possibly involving inhibitory or sensitizing intracellular molecules, such as SOC3, PTP-1B and SH2B1 respectively), with asymmetry as an adverse response (hormesis); this asymmetry is routed bilaterally via the sympathetic nervous system to the growing axial skeleton where it may initiate the scoliosis deformity (leptin-hypothalamic-sympathetic nervous system concept = LHS concept). In some younger preoperative AIS girls, the hypothalamic up-regulation to circulating leptin also involves the somatotropic (growth hormone/IGF) axis which exaggerates the sympathetically-induced asymmetric skeletal effects and contributes to curve progression, a concept with therapeutic implications. In the somatic nervous system, dysfunction of a postural mechanism involving the CNS body schema fails to control, or may induce, the spinal deformity of AIS in girls (escalator concept). Biomechanical factors affecting ribs and/or vertebrae and spinal cord during growth may localize AIS to the thoracic spine and contribute to sagittal spinal shape alterations. The developmental disharmony in spine and trunk is compounded by any osteopenia, biomechanical spinal growth modulation, disc degeneration and platelet calmodulin dysfunction. Methods for testing the theory are outlined. Implications are discussed for neuroendocrine dysfunctions, osteopontin, sympathoactivation, medical therapy, Rett and Prader-Willi syndromes, infantile idiopathic scoliosis, and human evolution. AIS pathogenesis in girls is predicated on two putative normal mechanisms involved in trunk growth, each acquired in evolution and unique to humans